We have continued our studies of the insulin-like growth factors (IGFs), their receptors, and binding proteins (IGFBPs) to understand the physiological and pathological role of the IGFs. IGF-I and IGF-II in plasma and other extracellular fluids occur complexed to IGFBPs, a family of at least 6 proteins that are thought to modulate IGF actions. We believe that a major component of this regulation occurs at the level of IGFBP synthesis in different tissues. The IGFBP-2 gene is expressed at higher levels in fetal than in adult rat tissues, especially liver, and persists in adult choroid plexus. IGFBP-2 mRNA is increased in liver in diabetes, fasting and growth hormone deficiency. We have isolated and characterized clones encoding the rat IGFBP-2 gene. Its promoter region lacks a TATA box, but contains potential cis regulatory elements for insulin regulation and liver-specific expression. Transcription of the IGFBP-1 gene is increased in diabetic rat liver, and decreased after insulin treatment. IGFBP-1 mRNA also is increased in fetal rat liver after maternal food deprivation. We have studied the regulation of IGFBP-1 gene expression in a model system, the well-differentiated H4-II-E rat hepatoma cell line. In H4-II-E cells, IGFBP-1 gene transcription is increased by the synthetic glucocorticoid dexamethasone, and rapidly (<20 min) decreased by physiological concentrations of insulin. The mammalian IGF-II/Mannose-6-phosphate receptor is a bifunctional receptor that binds IGF-II and proteins containing mannose-6-phosphate recognition markers (such as lysosomal enzymes). Chick embryo fibroblasts contain a primitive form of this receptor. It is the same size as and immunologically related to the mammalian IGF-II/Man 6-P receptor, binds and internalizes lysosomal enzymes, but does not bind IGF-II.